1. Technical Field
The invention relates to novel isoxazole derivatives, compositions comprising such compounds, and methods of preventing or treating conditions and disorders using such compounds and compositions.
2. Description of Related Technology
The endogenous cholinergic neurotransmitter, acetylcholine (ACh), exerts its biological effect via two types of cholinergic receptors, the muscarinic acetylcholine receptors (mAChR) and the nicotinic acetylcholine receptors (nAChR). nAChRs are pentameric assemblies of subunits surrounding a central pore that gates the flux of Na+, K+ and Ca2+ ions. At least 16 subunit proteins, i.e. α2-α10, β1-β10, γ, δ and ε, have been identified in neuronal tissues. These subunits provide for a great variety of homomeric and heteromeric combinations that account for the diverse receptor subtypes. For example, functional neuronal nAChR or neuronal nicotinic receptor (NNR) assemblies can be homomeric, comprising α7 or α8 or α9 subunits, or heteromeric, usually with at least one subunit from the α group (α2, α3, α4, α6) and the remainder from the β group (β2, β4). In the central nervous system, α4β2-containing NNR and α7-containing NNR subtypes are the most widespread and mediate synaptic and, possibly, paracrine functions. These NNRs are expressed at high levels in areas involved with learning and memory, and play key roles in modulating neurotransmission in these regions. Reduced cholinergic activity and dysregulation of NNRs have been correlated with disease states involving cognitive deficits, progressive dementia, and epilepsy. Accordingly, these NNRs are implicated in a range of physiological and patho-physiological functions related to cognitive function, learning and memory, reward, motor control, arousal and analgesia (reviewed in Gopalakrishnan, M. et al., Ion channels—Ligand-gated. Comprehensive Medicinal Chemistry II, Edited by Triggle D. J. et al., Major Reference Works, Elsevier. Unit 2.22, pp 877-918, 2006).
Discovery of the important roles played by NNRs in several CNS disorders has called attention to these membrane proteins and to ligands, or compounds, that are able to modulate, i.e. modify, the function of such membrane proteins. The prototypical NNR agonist, nicotine, has itself been shown to improve attention and cognitive performance, reduce anxiety, normalize sensory gating, and effect neuroprotection. However, nicotine is not sufficiently selective among NNRs and its utility is limited by side effects including seizures, irregular heartbeat, hypertension, and gastrointestinal effects. Accordingly, identification of compounds, agonists or allosteric modulators, that target distinct subtypes to retain the beneficial effects, while eliminating or decreasing adverse effects, continues to be an active area of research.
NNRs, especially α4β2 NNRs, have been targeted for pain, cognitive disorders and various central nervous system diseases. Gene knockout, antisense and pharmacological studies have shown that α4 and β2 NNRs are responsible for mediating nicotinic analgesia at supraspinal responses and spinal sites (Decker, M. W., et al., Curr. Top. Med. Chem., 4: 369-384, 2004). Ligands targeting α4β2 NNRs have shown improvement in cognitive and attentive function in preclinical models and, more recently, in human disease states such as attention deficit hyperactivity disorder (ADHD) (Wilens, T. E., et al., Biol. Pscyhiatry, 59: 1065, 2006) and age-associated memory impairment (Dunbar, G. C., et al., Psyschopharmacol., 21: 171, 2007). A key goal in the discovery of novel NNR compounds is to avoid ganglioinic α3* NNRs, as the dose-limiting emetic liability of nonselective compounds may be attributed to activation of α3 containing NNRs. α3* NNRs in the dorsal motor nucleus of the vagus and in nucleus tractus solitarius have been implicated in gastric and blood pressure responses to nicotine injected locally (Ferreira, M., et al., J. Pharmacol. Exp. Ther. 294:230-238, 2000).
Compounds with varying degrees of selectivity for α4β2 NNRs over other nicotinic subtypes (α3, α7, α1-containing) have been discovered over the years for the treatment of pain and a range of psychiatric and neurological disorders especially involving cognitive deficits in attention, alertness and memory. These may include those conditions that may benefit from selective enhancement of cholinergic transmission such as attention deficit, psychotic disorders, selected pain syndromes, smoking cessation and those thought to involve reduced cholinergic function such as neurodegenerative disorders, central inflammatory or autoimmune disorders, brain trauma and cerebrovascular disease. Modulation of α4β2 NNRs is expected to be beneficial in an number of diseases including Alzheimer's disease, mild cognitive impairment and related syndromes, Lewy body dementia, vascular dementia, attention deficit/attention deficit-hyperactivity disorder, schizophrenia, bipolar and mood disorders, schizoaffective disorders, Tourette's syndrome, brain trauma, vascular dementia, Parkinson's disease, Huntington's disease and conditions of substance abuse including alcohol abuse and smoking cessation. Selected pain syndromes includes chronic pain that can be nociceptive, neuropathic, or both and originating from cancer, injury, surgery, or chronic conditions such as arthritis or nerve injury/disease. Neuropathic pain can be peripheral (painful peripheral mononeuropathy and polyneuropathy) or central (post stroke, following spinal cord injury) and can originate from nerve injury following a wide array of conditions/events such as direct trauma to nerves, inflammation/neuritis/nerve compression, metabolic diseases (diabetes), infections (herpes zoster, HIV), tumors, toxins (chemotherapy), and primary neurological diseases.
Treatment with NNR agonists, which act at the same site, as the endogenous transmitter ACh, may be problematic because ACh not only activates, but also inhibits receptor activity through processes that include desensitization. Further, prolonged receptor activation may cause long-lasting inactivation. Thus, uncertainty exists whether chronic treatment with agonists in humans might provide suboptimal benefit due to sustained receptor activation and desensitization of the NNRs. An alternate approach to target α4β2 NNR function is by enhancing effects of the endogenous neurotransmitter acetylcholine via positive allosteric modulation. This approach provides an opportunity to (i) reinforce the endogenous cholinergic neurotransmission without directly activating the receptor like classical agonists, (ii) prevent receptor desensitization (iii) possibly resensitize inactivated receptors. Thus, the spatial and temporal characteristics of endogenous α4β2 receptor activation are preserved unlike agonists that will tonically activate all receptors, leading to a non-physiological pattern of receptor activation.
In light of the evidence supporting the various therapeutic uses of NNRs, it would be beneficial to discover novel allosteric modulators that could provide therapeutic benefits.